Senescence in Aging, Within the Brain and Other Diseases: Mechanisms and Interventions

Abstract

Aging, shifting demographics, and lifestyle changes are some of the underlying factors contributing to an increase in the incidence and prevalence of age-related disorders. Brain health is correlated with cellular senescence and is an important indicator of physiological aging and several age-related diseases. Examining the current state of knowledge of the underlying mechanisms of senescence as well as prospective therapeutic modalities concerning aging and age-related diseases is thus crucial. The senescence-associated secretory phenotype (SASP) of senescent cells (SnCs) results in a secretome, which is primarily composed of growth factors, cytokines/chemokines, and extracellular matrix (ECM) remodeling proteins secreted by the arrested cells. Increasingly, research suggests a causative role of senescence in various diseases such as osteoporosis, neurodegenerative diseases, cardiovascular diseases, and metabolic dysfunction, among others. SnCs promote age-related diseases by affecting the differentiation and proliferation of stem cells. They do so, in part through disruption of the Wingless-related integration site (Wnt) signaling pathways and Yes-associated protein and its ortholog transcriptional coactivators with a PDZ-binding domain (YAP/TAZ) transcriptional regulation, affecting tissue regeneration and a decreased ability for the body to rejuvenate. Senescent cell-induced immune system dysregulation, e.g., immunosenescence, as well as senescent cell-secreted substances also cause persistent, low-grade inflammation in organisms known as inflammaging, which accelerates aging and results in tissue damage. During age-related senescence, key chromatin structural changes take place in the cells that affect nuclear transport, causing genomic instability, changes in nucleosome positioning, post-translational modifications of histones, global histone loss, etc. Elimination of SnCS using senolytics by targeting cellular and molecular pathways has emerged as a potential therapeutic strategy for delaying aging and improving age-related dysfunctions including brain diseases.